A Randomized Comparison of Radial Artery Intimal Hyperplasia Following Distal Versus Proximal Transradial Access for Coronary Angiography: PRESERVE RADIAL.

BACKGROUND: Distal transradial access (dTRA) is an alternative to conventional forearm transradial access (fTRA) for coronary angiography (CAG). Differences in healing of the radial artery (RA) in the forearm have not been evaluated between these 2 access strategies. We sought to compare the mean difference in forearm RA intimal-medial thickening (IMT) in patients randomized to dTRA versus fTRA. METHODS AND RESULTS: In this single-center randomized clinical trial, 64 patients undergoing nonemergent CAG were randomized (1:1) to dTRA versus fTRA. Ultra-high-resolution (55-MHz) vascular ultrasound of the forearm and distal RA was performed pre-CAG and at 90 days. The primary end point was the mean change in forearm RA IMT. Secondary end points included procedural characteristics, vascular injury, RA occlusion, and ipsilateral hand pain and function. Baseline demographics and clinical characteristics, mean forearm RA IMT, and procedural specifics were similar between the dTRA and fTRA cohorts. There was no difference in mean change in forearm RA IMT between the 2 cohorts (0.07 versus 0.07 mm; P=0.37). No RA occlusions or signs of major vascular injury were observed at 90 days. Ipsilateral hand pain and function (Borg pain scale score: 12 versus 11; P=0.24; Disabilities of the Arm, Shoulders, and Hand scale score: 6 versus 8; P=0.46) were comparable. CONCLUSIONS: Following CAG, dTRA was associated with no differences in mean change of forearm RA IMT, hand pain, and function versus fTRA for CAG. Further investigation is warranted to elucidate mechanisms and predictors of RA healing and identify effective strategies to preserving RA integrity for repeated procedures. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04801901.

A Randomized Comparison of Radial Artery Intimal Hyperplasia Following Distal vs. Proximal Transradial Access for Coronary Angiography: PRESERVE RADIAL Trial.

Background: Distal transradial access (dTRA) is an alternative to conventional forearm transradial access (fTRA) for coronary angiography (CAG). Differences in healing of the radial artery in the forearm (FRA) have not been evaluated between these 2 access strategies. We sought to compare FRA intimal-medial thickening (IMT) in patients randomized to dTRA vs. fTRA for CAG. Methods and Results: Sixty-four consecutive patients undergoing non-emergent CAG were randomized (1:1) to dTRA vs. fTRA. Ultrahigh resolution (55 MHz) vascular ultrasound) of the FRA and distal RA was performed pre-CAG and at 90 days. Primary endpoint was 90-day FRA IMT. Secondary endpoints included procedural characteristics, vascular injury, RA occlusion and ipsilateral hand pain and function. Baseline demographics and clinical characteristics, mean FRA IMT, time to RA access, procedure time, and radiation exposure were similar between the dTRA and fTRA cohorts. There were no between group differences in 90-day FRA IMT (0.37 mm vs 0.38 mm, respectively; p =0.73). No RA occlusions or signs of major vascular injury were observed at 90 days. Ipsilateral hand pain and function (Borg pain scale:12 vs 11, p =0.24; DASH scores: 6 vs 8, p =0.46) were comparable. Conclusions: In this single center randomized clinical trial, similar patterns of FRA vascular healing at 90 days, procedural results as well as hand pain and function were observed following dTRA vs. fTRA for CAG. Further investigation is warranted to better understand the mechanistics and predictors of RA healing and to identify strategies aimed at preserving RA integrity for future procedures. What is New?: DTRA has been proposed as an alternative to traditional fTRA in the wrist for CAG and PCI because of ergonomic and post-procedural recovery benefits to the patient, as well as potential reductions in occlusion of the FRA.There are gaps in knowledge, however, regarding potential differences in remodeling of the FRA in patients undergoing dTRA versus fTRA.In this randomized clinical trial, there were no differences in IMT and patterns of vascular injury and healing, using ultrahigh resolution (55 MHz) ultrasound, at 90 days in patients randomized to dTRA or FTRA for elective and non-emergent CAG and PCI. What Are the Clinical Implications: Our findings highlight the need for further inquiry through large multicenter randomized clinical trials to better the understand the mechanistics and predictors of IMT and to identify strategies to mitigate the adverse effects of vessel remodeling in patients undergoing TRA across the entire severity spectrum of cardiovascular disease.

George Budd and His Contribution to the Early History of Amyloid Disease.

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A Standardized and Regionalized Network of Care for Cardiogenic Shock.

BACKGROUND: The benefits of standardized care for cardiogenic shock (CS) across regional care networks are poorly understood. OBJECTIVES: The authors compared the management and outcomes of CS patients initially presenting to hub versus spoke hospitals within a regional care network. METHODS: The authors stratified consecutive patients enrolled in their CS registry (January 2017 to December 2019) by presentation to a spoke versus the hub hospital. The primary endpoint was 30-day mortality. Secondary endpoints included bleeding, stroke, or major adverse cardiovascular and cerebrovascular events. RESULTS: Of 520 CS patients, 286 (55%) initially presented to 34 spoke hospitals. No difference in mean age (62 years vs 61 years; P = 0.38), sex (25% vs 32% women; P = 0.10), and race (54% vs 52% white; P = 0.82) between spoke and hub patients was noted. Spoke patients more often presented with acute myocardial infarction (50% vs 32%; P < 0.01), received vasopressors (74% vs 66%; P = 0.04), and intra-aortic balloon pumps (88% vs 37%; P < 0.01). Hub patients were more often supported with percutaneous ventricular assist devices (44% vs 11%; P < 0.01) and veno-arterial extracorporeal membrane oxygenation (13% vs 0%; P < 0.01). Initial presentation to a spoke was not associated with increased risk-adjusted 30-day mortality (adjusted OR: 0.87 [95% CI: 0.49-1.55]; P = 0.64), bleeding (adjusted OR: 0.89 [95% CI: 0.49-1.62]; P = 0.70), stroke (adjusted OR: 0.74 [95% CI: 0.31-1.75]; P = 0.49), or major adverse cardiovascular and cerebrovascular events (adjusted OR 0.83 [95% CI: 0.50-1.35]; P = 0.44). CONCLUSIONS: Spoke and hub patients experienced similar short-term outcomes within a regionalized CS network. The optimal strategy to promote standardized care and improved outcomes across regional CS networks merits further investigation.

Transradial access in acute myocardial infarction complicated by cardiogenic shock: Stratified analysis by shock severity.

BACKGROUND: Transradial access (TRA) is associated with improved survival and reduced vascular complications in acute myocardial infarction (AMI). Limited data exist regarding TRA utilization and outcomes for AMI complicated by cardiogenic shock (CS). We sought to assess the safety, feasibility, and clinical outcomes of TRA in AMI-CS. METHODS: One-hundred and fifty-three patients with AMI-CS were stratified into tertiles of disease severity using the CardShock score. The primary endpoint was successful percutaneous coronary intervention (PCI), defined as Thrombolysis in Myocardial Infarction III flow with survival to 30 days. RESULTS: Mean age was 66 years, 72% were men, and 47% had diabetes. TRA was the preferred access site in patients with low and intermediate disease severity. Overall, 50 (32%) patients experienced major adverse cardiac and cerebrovascular events; most events (78%) occurred in patients undergoing transfemoral access (TFA) in the intermediate-high tertiles of CS severity. Of the 41 (27%) total bleeding events, 32% occurred at the coronary angiography access site, of which 92% were in the TFA group. The use of ultrasound (US) guidance for TFA resulted in reduced coronary access-site bleeding (8.5 vs. 33.0%, p = .01). In a hierarchical logistic regression model, utilizing TRA did not result in lower odds of successful PCI (Odds ratio [OR]: 1.36; 95% confidence interval [CI]: 0.54-3.40). CONCLUSION: This study suggests that TRA is feasible across the entire spectrum of AMI-CS and is associated with reduced coronary access-site bleeding. In addition, US-guided TFA is associated with reductions in access-site bleeding and vascular complications. Concerted efforts should be made to incorporate vascular access protocols into existing CS algorithms in dedicated shock care centers.

Long-term effects of paliperidone palmitate on hospital stay and treatment continuation.

There is a growing need for real world data on long-term clinical and health resource utilization outcomes. The main purpose of this study was to establish the effects of 1-monthly Paliperidone Palmitate (PP1M) on treatment continuation and hospital stay in routine clinical practice. This is a naturalistic, 6-year mirror-image study examining retention and hospitalization rates 3 years pre-PP1M and 3 years post-PP1M initiation. One hundred seventy-three patients were included; 120 (70%) had a primary diagnosis of schizophrenia and 53 (30%) other diagnosis. In total, 77% of patients continued PP1M for one year, 66% for two years and 55% for three years. For the patients who continued with PP1M for 3 years (n = 95), the mean number of hospital admissions decreased significantly from 1.44 to 0.53 and the mean number of bed days from 93 to 29 bed days 3 years before and 3 years after PP1M initiation (P < 0.001). The group of patients with schizophrenia who continued for 3 years (n = 79) demonstrated similar outcomes. The introduction of PP1M had a significant impact on long-term clinical outcomes. More than half of patients were still continuing on PP1M at 3 years after initiation and had no admission during 3 years follow-up.

Outcomes among patients requiring unplanned intra-aortic balloon pump reinsertion in cardiogenic shock.

INTRODUCTION: The intra-aortic balloon pump (IABP) is the most frequently utilized form of temporary mechanical circulatory support (MCS) in cardiogenic shock (CS). Withdrawal of IABP support may precipitate hemodynamic compromise such that IABP reinsertion is required. Data are scarce regarding the incidence and outcomes of patients undergoing IABP reinsertion in this setting. METHODS: In this single-center retrospective study, we identified consecutive patients with CS in whom IABP reinsertion was required for hemodynamic decompensation. These patients were compared to matched controls in whom IABP withdrawal was successful. The primary outcome measure was in-hospital mortality, while the secondary outcome measure was a composite of in-hospital death, need for advanced MCS or heart transplantation, or discharge to hospice. RESULTS: Among 222 patients requiring IABP for CS, we identified 20 case patients (incidence=9.0%) and 38 matched controls. Baseline characteristics were similar for the two groups. In-hospital mortality was 70% in the reinsertion group and 31% in the controls (Odds ratio (OR) 5.2, 95% CI 1.4-18.9, P=0.005). The composite secondary endpoint was also significantly more common in the reinsertion group than the controls (85% vs. 42%; OR 7.3, 95% CI 1.6-33.1, P=0.002). On multivariate analysis, the need for IABP reinsertion was independently associated with in-hospital mortality (OR 7.7, 95% CI 1.6-36.2, P=0.01). CONCLUSION: Among patients with CS undergoing IABP removal, hemodynamic deterioration requiring IABP reinsertion is associated with extremely poor outcomes and, in appropriate patients, should prompt consideration of more advanced cardiac support.

Vstm3 is a member of the CD28 family and an important modulator of T-cell function.

Members of the CD28 family play important roles in regulating T-cell functions and share a common gene structure profile. We have identified VSTM3 as a protein whose gene structure matches that of the other CD28 family members. This protein (also known as TIGIT and WUCAM) has been previously shown to affect immune responses and is expressed on NK cells, activated and memory T cells, and Tregs. The nectin-family proteins CD155 and CD112 serve as counter-structures for VSTM3, and CD155 and CD112 also bind to the activating receptor CD226 on T cells and NK cells. Hence, this group of interacting proteins forms a network of molecules similar to the well-characterized CD28-CTLA-4-CD80-CD86 network. In the same way that soluble CTLA-4 can be used to block T-cell responses, we show that soluble Vstm3 attenuates T-cell responses in vitro and in vivo. Moreover, animals deficient in Vstm3 are more sensitive to autoimmune challenges indicating that this new member of the CD28 family is an important regulator of T-cell responses.

Clinical implications of thrombocytopenia among patients undergoing intra-aortic balloon pump counterpulsation in the coronary care unit.

BACKGROUND: Thrombocytopenia Hypothesis: intra-aortic balloon pump (IABP)-associated thrombocytopenia is not associated with an increased risk of major bleeding or in-hospital death. Thrombocytopenia is a common adverse effect of the IABP. However, the clinical implications of IABP-associated thrombocytopenia are unknown. METHODS: We assessed the incidence and predictors of thrombocytopenia, and the association between thrombocytopenia and relevant clinical end points, using prospectively collected data on 252 consecutive patients undergoing IABP in a single coronary care unit (CCU). RESULTS: Anticoagulation with intravenous heparin was administered to 182 patients (72%). Baseline platelet counts were 232 000 +/- 96 000 mL, decreased to 154 000 +/- 74 000 mL at day 3, and recovered to baseline by day 8. Thrombocytopenia (nadir < 150 000 mL or > 50% reduction from baseline) occurred in 109 patients (43%), with a similar incidence among patients who received heparin and those who did not (45% vs 40%, P = 0.5). Independent predictors of thrombocytopenia were lower body weight, cardiogenic shock, and duration of IABP support. The incidence of both major bleeding and in-hospital death were higher among patients who developed thrombocytopenia than among those who did not (13.8% vs 4.2%, P = 0.01 and 28% vs 16%, P = 0.02, respectively). However, after controlling for confounding variables, thrombocytopenia was not an independent predictor of either major bleeding (odds ratio [OR]: 2.2, 95% confidence interval [CI]: 0.8-6.4, P = 0.1) or in-hospital death (OR: 1.5, 95% CI: 0.8-2.9, P = 0.3). CONCLUSIONS: Among patients undergoing IABP in the CCU, thrombocytopenia is generally mild, appears to be unrelated to concomitant heparin use, and is not associated with an increased risk of major bleeding or in-hospital death.

Clinical studies on anorectal myectomy for chronically constipated patients with outlet obstruction in childhood.

BACKGROUND/AIMS: To clarify the significance of anorectal myectomy (ARM) for chronically constipated patients with outlet obstruction (CCPOO) in childhood, we analyzed the clinical features of theses patients before and after ARM. METHODOLOGY: A consecutive series of one hundred and seven patients with CCPOO were included in this study. These were fifty-eight males and forty-nine females, aged between 0.2 and 15 years with a mean age of 8.9 years. We performed an analysis of the clinical findings and outcomes for CCPOO before and after ARM. RESULTS: More than half of the patients were under the age of 6. Neurohistochemical study showed hypoganglionosis (Hypo) in 71 patients [mild type (3/5 or more ganglion cells per ganglia): 51 cases, severe type (less than 2/5 ganglion cells per ganglia): 20 cases], normal ganglia in 29, intestinal neuronal dysplasia (IND) in 2, and Hirschsprung's disease (HD; aganglionosis) in 5 (3 cases were residual HD after Soave's or Duhamel's operation). Most of the patients were Hypo, followed by those who were normal and finally those who had other histological types (HD and IND) in decreasing order. Mild Hypo was the most common compared with normal ganglia and HD (P<0.001, P<0.00001, respectively). Abdominal pain was the most common symptom, followed by soiling and anal pain. In addition, abdominal pain was the most common complaint in Hypo patients, and severe Hypo patients had abdominal pain more frequently than those with mild Hypo (P<0.05). The most common outcome after ARM was good (72.0%), followed by poor (15.9%) and satisfactory (12.1%) in decreasing order. There were significant differences between good and satisfactory, and between good and poor (P<0.0001, respectively). In addition, good was the most common outcome in mild Hypo patients compared with severe Hypo (P<0.0001). Poor was the most common outcome in severe Hypo patients compared with mild Hypo (P<0.001). Spontaneous evacuation was recorded in 72.7% of good outcome patients, and 38.5% of those with satisfactory outcome after ARM. Regarding the use of laxatives, there were significant differences between good and satisfactory, between satisfactory and poor, and between good and poor outcome (P<0.05, P<0.01, P<0.0001, respectively). Colonic, psychological or central nervous disorders were found at high rates in patients with poor outcome. The most common related cause of constipation after ARM was a redundant colon. CONCLUSIONS: Hypo, IND, and HD may be largely related to defecation disorders observed in childhood CCPOO. CCPOO patients with colonic disorders, psychological or central nervous disorders may experience significant persistent constipation after ARM.

Surgical outcome in biliary atresia: etiology affects the influence of age at surgery.

OBJECTIVE: The exact nature of the relationship between age at Kasai portoenterostomy (KP) for biliary atresia (BA) and outcome is controversial. METHODS: Single-center retrospective analysis of consecutive cases (January 1994-December 2005) undergoing KP, using 2 dichotomous measures of outcome (clearance of jaundice to <20 micromol/L and native liver survival at 2 years post-KP). Outcome was analyzed by age cohort (<30 days, 30-40 days, etc) and cumulatively. Data are quoted as median (interquartile range). Statistical analysis was by extended Fisher r x c analysis. P < 0.05 was regarded as significant. RESULTS: Two hundred twenty-five infants with BA were divided into 3 groups based on possible etiology: isolated BA (n = 177), biliary atresia splenic malformation (BASM) syndrome (n = 28), and cystic BA (n = 23). Three infants had both BASM and a cyst. Age at KP was significantly greater in those with isolated BA [58 (48-61)] compared with both BASM [47 (39-59); P = 0.02] and cystic BA [47 (39-54); P = 0.02]. Overall, 127 (56%) cleared their jaundice and 145 (65%) survived to 2 years with their native liver. Children with isolated BA showed no statistical difference by age cohort for clearance of jaundice (P = 0.75) or for native liver survival (P = 0.14). In contrast, there was a marked detrimental effect of age at KP for both BASM and cystic BA groups (P = 0.02). CONCLUSION: There is a marked detrimental effect of age at KP on groups with a presumed "developmental" origin, not seen in the majority with isolated BA.

Decreased adhesiveness, resistance to anoikis and suppression of GRP94 are integral to the survival of circulating tumor cells in prostate cancer.

The presence of circulating tumor cells (CTC) is common in prostate cancer patients, however until recently their clinical significance was unknown. The CTC stage is essential for the formation of distant metastases, and their continuing presence after radical prostatectomy has been shown to predict recurrent or latent disease. Despite their mechanistic and prognostic importance, due both to their scarcity and difficulties in their isolation, little is known about the characteristics that enable their production and survival. The aim of this study was to investigate the molecular mechanisms underlying the survival of CTC cells. A novel CTC cell line from the bloodstream of an orthotopic mouse model of castration-resistant prostate cancer was established and compared with the primary tumor using attachment assays, detachment culture, Western blot, flow cytometry and 2D gel electrophoresis. Decreased adhesiveness and expression of adhesion molecules E-cadherin, beta4-integrin and gamma-catenin, together with resistance to detachment and drug-induced apoptosis and upregulation of Bcl-2 were integral to the development of CTC and their survival. Using proteomic studies, we observed that the GRP94 glycoprotein was suppressed in CTC. GRP94 was also shown to be suppressed in a tissue microarray study of 79 prostate cancer patients, indicating its possible role in prostate cancer progression. Overall, this study suggests molecular alterations accounting for the release and survival of CTC, which may be used as drug targets for either anti-metastatic therapy or the suppression of latent disease. We also indicate the novel involvement of GRP94 suppression in prostate cancer metastasis.

Evidence of a novel docetaxel sensitizer, garlic-derived S-allylmercaptocysteine, as a treatment option for hormone refractory prostate cancer.

The recent introduction of docetaxel in the treatment of hormone refractory prostate cancer (HRPC) has made a small but significant impact on patient survival. However, its effect is limited by intolerance and resistance. The aim of our study was to investigate if the garlic-derived compound, S-allylmercaptocysteine (SAMC), was able to act as a docetaxel sensitizing agent. First, the effect of SAMC on docetaxel sensitivity was examined on 3 HRPC cell lines by colony forming assay. We found that SAMC increased the efficacy of docetaxel on colony forming inhibition by 9-50% compared to single agent treatment. Second, using the HRPC CWR22R nude mice model, we found that the combination of SAMC and docetaxel was 53% more potent than docetaxel alone (p = 0.037). In addition, there was no additive toxicity in the mice treated with the combination therapy evidenced by histological and functional analysis of liver, kidney and bone marrow. These results suggest that SAMC is able to increase the anticancer effect of docetaxel without causing additional toxic effect in vivo. Third, flow cytometry and Western blotting analysis on HRPC cell lines demonstrated that SAMC promoted docetaxel-induced G2/M phase cell cycle arrest and apoptotic induction. In addition, immunohistochemistry on CWR22R xenograft revealed a suppression of Bcl-2 expression and upregulation of E-cadherin in the SAMC and docetaxel treated animals. These results suggest that SAMC may promote docetaxel-induced cell death through promoting G2/M cell cycle arrest and apoptosis. Our study implies a potential role for SAMC in improving docetaxel based chemotherapy for the treatment of HRPC.

Pathophysiological role of the cholinergic and adrenergic nerves in patients with allied disorders of Hirschsprung's disease (intestinal neuronal dysplasia and hypoganglionosis)--an in vitro experiment.

BACKGROUND/AIMS: There are no reports about the pathophysiological roles of cholinergic and adrenergic nerves in the intestines of patients with allied disorders of Hirschsprung's disease (HD) such as intestinal neural dysplasia (IND) and hypoganglionosis (Hypo). To clarify the significance of the cholinergic and adrenergic nerves in Hypo and IND, we investigated enteric nerve responses to acetylcholine (Ach) and noradrenaline (NA) in colonic tissues obtained from patients with these diseases. METHODOLOGY: Colonic tissue specimens were obtained from 8 patients with HD (aganglionosis; 4 boys and 4 girls, aged 6 months to 3 years), 4 patients with Hypo (4 boys, aged 9 months to 3 years and 5 months), and 3 patients with IND (3 boys, aged 6 months to 3 years). Colon specimens from 8 patients without constipation (5 boys and 3 girls, aged 4 to 12 years) were used as controls. A mechanograph was used to evaluate in vitro colonic responses to electrical field stimulation (EFS), Ach, and NA. RESULTS: All muscle strips showed responses to EFS. Tetrodotoxin almost abolished the EFS responses in all the muscle strips. According to these results, we ascertained that the enteric nervous system was present in all muscle strips. 1) Ach showed a contraction reaction. The frequency of the contraction reaction in normal colon was highest, followed by those in IND colon, Hypo colon, and HD colon in decreasing order. In addition, significant differences were noted between the frequency of the contraction reaction in normal colon and those in IND colon, Hypo colon and HD colon (p < 0.01, p < 0.001, p < 0.0001, respectively). 2) NA showed a relaxation reaction. The frequency of relaxation reaction in normal colon was highest, followed by those in IND colon and Hypo colon in decreasing order. HD colon showed no response. In addition, significant differences were noted between the frequency of the relaxation reaction in normal colon and those in IND colon, Hypo colon and HD colon (p < 0.05, p < 0.001, p < 0.0001, respectively). There was also a significant difference between IND colon and HD colon (p < 0.05). CONCLUSIONS: The diminution of action of cholinergic and adrenergic nerves may be largely related to the impaired motility observed in IND, Hypo, and HD.

Assessments of anorectal myectomy for short segment hypoganglionosis in childhood.

BACKGROUND/AIMS: To clarify the significance of anorectal myectomy (ARM) in childhood patients with short segment hypoganglionosis (Hypo), we analyzed the clinical features of these patients before and after ARM. METHODOLOGY: A consecutive series of twenty-nine patients with short segment Hypo were included in this study. These were sixteen males and thirteen females, aged between 6 and 15 years with a mean age of 9.8 years. We performed an analysis of the clinical findings and outcomes for patients with short segment Hypo before and after ARM. Stool frequencies were less than twice per week (0.5-2 per week, mean: 1.6 per week) despite the use of laxatives, suppositories, and enema before ARM. RESULTS: About 90% of patients had an onset of constipation before the age of 6 years. In addition, significant differences were noted between 0 months < or = to <1 year and 1 year < or = to < or =15 years (P < 0.0001). There were no sexual differences. Difficulty in defecation was the most common symptom, followed by abdominal fullness, abdominal pain and soiling. In abdominal fullness and pain, there were significant differences between positive and negative groups (P < 0.0001, P = 0.0038, respectively). No patients responded to use of laxatives, suppositories, and enema before ARM. In patients after ARM, the most common outcome was good (65.5%; bowel movement every day without laxatives and no other symptoms), followed by satisfactory (20.7%; bowel movement 2-3 times per week without laxatives and no other symptoms) and poor (13.8%; no improvement) in decreasing order. Significant differences of patient numbers were noted between good and the remaining outcomes (P = 0.0181). Spontaneous evacuation without the need for laxatives, suppositories, and enema was recorded in 100% patients of good outcome, and 42.9% those of satisfactory outcome after ARM. Patients with poor outcome still required for laxatives, suppositories, and enema. Central nervous, psychological, and psychiatric disorders were recognized in patients with satisfactory outcome, and constipation was maintained to these patients. However, the necessity for medication to them was lost. Moreover, clinical symptoms disappeared. Redundant colon was only found in patients with poor outcome. CONCLUSIONS: Patients with short segment Hypo, especially those with redundant colon, psychological, psychiatric, or central nervous disorders, may experience persistent constipation after ARM.

Garlic-derived S-allylmercaptocysteine is a novel in vivo antimetastatic agent for androgen-independent prostate cancer.

PURPOSE: There is epidemiologic evidence that high garlic consumption decreases the incidence of prostate cancer, and compounds isolated from garlic have been shown to have cancer-preventive and tumor-suppressive effects. Recent in vitro studies in our laboratory have shown that garlic-derived organosulfur compound S-allylmercaptocysteine suppresses invasion and cell motility of androgen-independent prostate cancer cells via the up-regulation of cell-adhesion molecule E-cadherin. S-allylmercaptocysteine is therefore a potential antimetastatic drug with broad clinical applications that we tested in vivo for the first time in this study. EXPERIMENTAL DESIGN: We used a newly established fluorescent orthotopic androgen-independent prostate cancer mouse model to assess the ability of S-allylmercaptocysteine to inhibit tumor growth and dissemination. RESULTS: We showed that oral S-allylmercaptocysteine not only inhibited the growth of primary tumors by up to 71% (P < 0.001) but also reduced the number of lung and adrenal metastases by as much as 85.5% (P = 0.001) without causing notable toxicity. This metastatic suppression was accompanied by a 91% reduction of viable circulating tumor cells (P = 0.041), suggesting that S-allylmercaptocysteine prevents dissemination by decreasing tumor cell intravasation. CONCLUSIONS: Our results provide in vivo evidence supporting the potential use of S-allylmercaptocysteine as an E-cadherin up-regulating antimetastatic agent for the treatment of androgen-independent prostate cancer. This is the first report of the in vivo antimetastatic properties of garlic, which may also apply to other cancer types.

A novel mutation in CD83 results in the development of a unique population of CD4+ T cells.

Using a mouse mutagenesis screen, we have identified CD83 as being critical for the development of CD4(+) T cells and for their function postactivation. CD11c(+) dendritic cells develop and function normally in mice with a mutated CD83 gene but CD4(+) T cell development is substantially reduced. Additionally, we now show that those CD4(+) cells that develop in a CD83 mutant animal fail to respond normally following allogeneic stimulation. This is at least in part due to an altered cytokine expression pattern characterized by an increased production of IL-4 and IL-10 and diminished IL-2 production. Thus, in addition to its role in selection of CD4(+) T cells, absence of CD83 results in the generation of cells with an altered activation and cytokine profile.

Histological studies on Hirschsprung's disease and its allied disorders in childhood.

BACKGROUND/AIMS: To obtain accurate diagnosis for Hirschsprung's disease (HD) and its allied disorders such as hypoganglionosis (Hypo) and intestinal neuronal dysplasia (IND) in childhood patients with chronic constipation, we studied the histology of childhood patients with refractory constipation accompanied by abdominal distension and pain. METHODOLOGY: Based on clinical signs and symptoms noted on admission, all of 109 patients (60 males and 49 females, aged 2-15 years with a mean age of 9.8 years) were suspected to have chronic refractory constipation. To obtain accurate histological diagnosis in childhood patients with chronic refractory constipation, we performed rectal biopsies on these patients. Tissue samples were frozen and 12-microm sections were stained with acetylcholinesterase (AChE) by the method of Karnovsky and Roots, and with nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase by the modified Scherer-Singler's method. RESULTS: On the basis of histological studies using rectal biopsies, 20 cases were diagnosed with Hypo, 5 with HD, 2 with intestinal neuronal dysplasia (IND), and 82 with normal findings. The incidence of normal cases was significantly greater than that of allied disorders of HD including both Hypo and IND (P<0.0001). The incidence of Hypo was also significantly greater than that of Hypo and IND (P<0.01, P<0.0001, respectively). Both HD and IND could be diagnosed by rectal mucosal biopsies with AChE staining. However, accurate diagnosis of Hypo could be made only through examination of the submucosal and myenteric plexuses by NADPH-diaphorase staining in full-thickness rectal specimens. CONCLUSIONS: We were able to obtain accurate diagnosis of childhood patients with HD and IND by rectal mucosal biopsy with AChE staining. On the other hand, accurate histological diagnosis in patients with Hypo could also be obtained by NADPH-diaphorase staining in full-thickness rectal specimens. That is to say, it is easier for the investigator to detect the cholinergic fiber and ganglion cell in the gut wall using NADPH-diaphorase staining than by using AChE staining.

Long-term survival following Kasai portoenterostomy: is chronic liver disease inevitable?

OBJECTIVES: Extrahepatic biliary atresia (EHBA) is the most common indication for liver transplantation in childhood. Most children who do not undergo transplant are reported to have chronic liver disease and its complications. The aim of this single-center study was to identify children with normal laboratory indices and no clinical evidence of chronic liver disease 10 or more years after Kasai portoenterostomy (KP). METHODS: A retrospective analysis of the medical notes of all children surgically treated at the authors' center between 1979 and 1991 was undertaken. Criteria for inclusion were absence of surgical complications, unremarkable clinical examination, and normal bilirubin, aspartate aminotransferase, albumin, international normalized prothrombin ratio, and platelet count. RESULTS: Of 244 children surgically treated during the observation period, the authors identified 28 (11%) adolescents (14 male) who fulfilled the entry criteria. Their median age was 13.4 years (range, 10.2-22.2 years). Twenty-six with type 3 EHBA had conventional KP, whereas 2 underwent modified operations. The corrective surgery was performed at a median age of 58 days (range, 20-99 days). Median time of complete clearance of jaundice from the date of KP was 75 days (range, 21-339 days). Twelve (43%) patients had history of cholangitis at a median age of 3.4 years. The liver histologic findings were suggestive of mild to moderate fibrosis in 54.2% and cirrhosis in 40.7% of the patients who underwent biopsy. No child had gastrointestinal bleeding during follow-up. Thirteen (46%) patients had an elective esophagogastroduodenoscopy, which was normal in all. Twenty-six (93%) patients were in mainstream education, whereas the remaining two (7%) attended special school because of reasons unrelated to liver disease. CONCLUSIONS: A sizable proportion of children with EHBA avoid significant chronic liver disease and its complications 10 years or more after conventional surgical correction and have an excellent quality of life. Their good outcome is not hampered by isolated episodes of ascending cholangitis. Whether or not the residual histologic damage will become symptomatic during their lifetime remains to be established.